Molecular Oxygen-Promoted General and Site-Specific Alkylation with Organoboronic Acid

Article abstract of DOI:10.1021/acs.joc.8b02277

A general alkylating method using organoboronic acid under 1 atm of oxygen is developed. It allows a facile access to a wide range of functionalized molecules with privileged scaffolds in drugs and natural products such as oxindoles, quinolinones, chromon

Full text of DOI:10.1021/acs.joc.8b02277

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Article
A Molecular Oxygen-Promoted General and Site-
Specific Alkylation with Organoboronic Acid
Anbo Ling, Lizhi Zhang, Ren Xiang Tan, and Zhong-Quan Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02277 • Publication Date (Web): 15 Nov 2018
Downloaded from http://pubs.acs.org on November 15, 2018
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A Molecular Oxygen-Promoted General and Site-Specific Alkylation
with Organoboronic Acid
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Anbo Ling † Lizhi Zhang † Ren Xiang Tan‡ and Zhong-Quan Liu* †‡
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† State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
‡ State Key Laboratory Cultivation Base for TCM Quality and Efficacy, College of Pharmacy, Nanjing
University of Chinese Medicine, Nanjing 210023, China
Ar2
R
R2
O
FG
R
N
O
O
FG
N
O
R
O
R1
O
O
Ar1
N
Ar2
O
FG
N
R B(OH)2
1 atm O2
R1 R2
O
O
H
N
O
O
O
FG
O
O
FG
H
N
R
FG
O
O
R
R
FG
O
R
site-specific
42 examples
43-90% yields metal-free chemical oxidant-free
Abstract: A general alkylating method using organoboronic acid under 1 atm. of
oxygen is developed. It allows a facile access to a wide range of functionalized
molecules with privileged scaffolds in drugs and natural products such as oxindoles,
quinolinones, chromones, naphthoquinones, coumarins, and quinolones. In contrast to
previous alkylation approaches that generally requiring transition-metal catalysis and
stoichiometric chemical oxidant, the present strategy features metal-free, molecular
oxygen as the terminal oxidant and site-specificity.
INTRODUCTION
Combustion of triethylborane could produce a beautiful green flame, which was
considered as the first report on reaction of organoborane with molecular oxygen by
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Frankland in 1860.1 Studies on free radical chemistry of organoborane sprang up till
one century later. Since then authoxidation of trialkylborane has become one of the
most important initiating system for free radical reactions.2 As carbon-centered radical
precursors, trialkylboranes3 and organotrifluoroborates4 have been widely utilized to
form C-C bonds. In contrast, more stable organoboronic acids are rarely used as a
radical source. The reaction of molecular oxygen with boronic acid was firstly
reported by Davies and Roberts in 1966.5 They found that optically pure
1-phenylethylboronic acid was oxidized to racemic peroxides by oxygen. And then
they suggested the autoxidation of organoborane would undergo a radical-chain
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2-
process. Fifty-four years later, a facile Ag(I)/S2O8 -mediated Minisci-type C-C
formation by using R(Ar)-B(OH)2 was demonstrated by Baran and co-workers.6
Subsequently, Chatani7 and Rodríguez8 achieved convenient alkylation of isonitrile
and arene with alkylboronic acid by stoichiometric Mn(III), respectively. In 2013, an
efficient (sp3)C-H arylation with arylboronic acid by Ni(II)/DTBP was developed by
Lei.9 Two years later, Antonchick and Bering found that hot DMSO could enable aryl
boronic acid to realize arylation of quinoline N-oxide.10 Recently, an effective
Ru(II)/hypervalent iodine-triggered photoredox alkylation of heterocycle using
alkylboronic acids was explored by Chen.11 Very recently, we realized a first
O2-promoted heteroaromatic C-H alkylation by using boronic acids.12 Herein, we
wish to report a molecular oxygen-mediated radical alkylation and/or alkylarylation of
activated alkenes with organoboronic acids (Scheme 1). It could allow a general,
metal-free and stoichiometric chemical oxidant-free access to structurally diverse
heterocycles such as alkylated oxindoles,13 3,4-dihydroquinolin-2(1H)-ones,14
chromones, coumarins, quinolones, and naphthoquinones.15 These molecules are
well-known as biologically active compounds with privileged scaffolds for library
design and drug discovery (Scheme 1).16 To the best of our knowledge, this work
represents the first applicable alkylation and/or alkylarylation of alkenes by using
organoboronic acids and O2.
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2-
Ag(I)/S2O8
;
Mn(III); Ru(II)/I(III)
1 atm O2 only
R
B(OH)2
R B(OH)2
R
previous strategies
this strategy
7
8
9
O
HO
HO
H
O
O
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Cl
O
O
NH
N
HO
O
OMe
O
H
N
OH
virantmycin
urachromone B
alstonisine
O
O
O
O
O
NO2
F
CO2H
N
N
3
3
3
OH
HN
H
H
O
acenocoumarol
ciprofloxacin
Vitamin K1
Scheme 1. Alkyl Radical Generation Using Alkylboronic Acid as Precursor and Relevant
Biologically Active Molecules.
RESULTS AND DISCUSSION
Molecular oxygen based oxidation17 and transformations18 represent the most clean
and sustainable processes. As our continuous endeavors for developing highly
efficient radical synthetic methods,19 we found that reaction of alkylboronic acid with
O2 could afford alkyl radical by heating.12 Then we began to envision whether it could
realize a general C-C bond formating method. In order to test this hypothesis, radical
addition/cyclization cascade reaction of N-arylacrylamide with RB(OH)2 was initially
carried out to optimize the reaction conditions (Table 1). We found that additive,
solvent and temperature are important to this system. Firstly, a series of solvents were
screened (entries 1-7). To our delight, the desired product 1 was isolated in an
excellent yield in a mixed solvent (entry 7). Next, we evaluated the effect of the acid
additive (entries 10-12). The products were obtained in 50% yield without TFA and
47% yield without any acids. The yield increased to 62% by addition of 1 equivalent
of TFA. The results indicate that acids could promote this process. Subsequently, we
examined the effect of temperature for this transformation (entries 13 and 14). As a
result, the reactions under 80oC and 100oC gave the corresponding products in 47%
and 65% yields, respectively. Finally, we observed that a decreased yield of 1 was
obtained by decreasing the amount of boronic acid (entry 15). No reaction occurred
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under nitrogen atmosphere (entry 16).
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Table 1. Optimization of the Reaction Conditionsa
8
9
O
O
1 atm
2
+
B(OH)2
N
additive
solvent
10
11
12
13
14
15
16
17
18
19
20
21
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42
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48
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50
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53
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56
57
58
59
60
N
1
entry additive (equiv)
solvent (mL)
DCE (0.5)
T (oC) yield (%)b
1
2
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
-
110
110
110
110
110
110
52
35
40
69
82
79
90
77
82
50
47
62
47
65
76
0
t-BuOH (0.5)
3
EtOH (0.5)
4
CH3CN (0.5)
5
EtOH/DCE (0.25/0.25)
HOAc/DCE (0.25/0.25)
6
7
HOAc/CH3CN (0.25/0.25) 110
8
HOAc/CH3CN (0.2/0.2)
HOAc/CH3CN (0.3/0.3)
HOAc/CH3CN (0.25/0.25)
CH3CN (0.5)
110
110
110
110
110
80
9
10
11
12
13
14
15c
16d
-
TFA (1)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
HOAc/CH3CN (0.25/0.25)
HOAc/CH3CN (0.25/0.25)
HOAc/CH3CN (0.25/0.25)
HOAc/CH3CN (0.25/0.25)
HOAc/CH3CN (0.25/0.25)
100
100
110
a
Reaction conditions: N-methyl-N-phenylmethacrylamide (0.2 mmol, 1 equiv), cyclohexylboronic
b
c
acid (1 mmol, 5 equiv), 1 atm O2 (oxygen bag), 6 h, unless otherwise noted. Isolated yields.
cyclohexylboronic acid (0.8 mmol, 4 equiv). d N2 instead of O2.
With the above informations in hand, we then start to investigate the substrate
scope. It can be seen from Scheme 2 that a wide range of N-arylacrylamides and alkyl
boronic acids could afford the corresponding oxindoles in moderate to high yields.
Both electron-donating and electron-withdrawing groups as well as halogens (F, Cl,
Br, and I) on the aromatic core in N-arylacrylamides gave the desired products in
good yields (2-13). Poly-substituents at ortho-, meta-, and para-position of
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N-arylacrylamides also led to acceptable yield of the oxindoles, which indicated that
the steric effect was not remarkable. Furthermore, N,N-diphenylmethacrylamide,
N-methyl-N-(naphthalen-1-yl)methacrylamide, and 2-(methyl(phenyl)carbamoyl)allyl
acetate afforded the corresponding products in good yields (14-16). Finally, an array
of alkylboronic acids were evaluated (17-21). And we found that both linear and
cyclic alkyl boronic acids gave the desired oxindoles in moderate to good yields.
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11
12
13
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15
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60
Scheme 2. O2-Promoted Alkylarylation of alkenes with Alkyl Boronic Acids.a
R2
O
R
O
O
1 atm
2
FG
+ R B(OH)2
FG
N
TFA, HOAc/MeCN
110 oC, 6 h
N
R1
R1 R2
MeO
O
O
O
N
N
N
b
2
3
, 85%
, 69%
1
, 90%
Cl
F
Br
O
O
O
N
N
N
5
, 84%
4
6
, 82%
, 68%
I
NC
O
O
O
N
N
N
7
9
, 62%
, 70%
8
, 65%
MeO
O
O
O
N
N
N
OMe
OMe
10
11
, 82%
, 63%
12
, 74%
Br
O
O
O
N
N
N
Ph
, 68%
Cl
14
13
, 43%
15
, 64%
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AcO
5
6
7
8
O
N
O
O
N
N
9
18
, 78%
17
, 60%
16
, 72%
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16
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60
O
O
O
N
N
N
19
, 75%
21
, 57%
20
, 61%
a
Reaction conditions: N-arylacrylamide (0.2 mmol, 1 equiv), alkyl boronic acid (5 equiv, 1 mmol),
TFA (2 equiv, 0.4 mmol), HOAc (0.25 mL), CH3CN (0.25 mL), 1 atm O2 (oxygen bag), 110oC
(measured temperature of the oil bath), 6 h, unless otherwise noted. b Isolated yields.
Next, various kinds of molecules containing activated C=C double bonds were
evaluated under the typical reaction conditions (Scheme 3). First, a series of
N-methyl-N-arylcinnamamides were found to be effective substrates, and the
corresponding alkylated 3,4-dihydroquinolin-2(1H)-ones were smoothly obtained via
this radical addition/cyclization cascade strategy (22-27). It is noteworthy that the
chemoselectivities
are
extremely
high.
Only
anti-isomers
of
3-cyclohexyl-1-methyl-4-aryl-3,4-dihydroquinolin-2(1H)-ones were observed, which
should be due to the radical stability and steric effect. Then several chromones were
examined. As a result, site-specific alkylated chromones (28-30) were isolated in
45-53% yields. The relatively nucleophilic alkyl radical trends to attack the
electron-deficient C2 position, which might be responsible for the site-selectivity.
Subsequently, an array of coumarins and quinolones were examined to be also
amenable to this system. The desired 3-alkyl-2H-chromen-2-ones as well as 3-alkyl
quinolin-2(1H)-ones were facilely synthesized in moderate to good yields (31-39).
Gratifyingly, site-specific alkylation occurred at C3 position, which should be due to
the generation of more stable benzyl radical intermediate. Finally, dialkylation
products were obtained with 1,4-naphthoquinones (40-42). Interestingly,
naphthalene-1,4-dione and 2-methylnaphthalene-1,4-dione afforded dialkyl addition
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products (40 and 41) while 2-chloronaphthalene-1,4-dione gave the
addition/elimination dialkyl 1,4-naphthoquinone (42). Overall, diverse alkyl
heterocycles could be synthesized by this protocol.
9
Scheme 3. O2-Promoted Alkylarylation and/or alkylation of activated alkenes
with Alkyl Boronic Acids.a
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13
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Ar2
O
Ar1
O
O
N
Ar2
FG
N
O
O
O
O
O
O
O
O
B(OH)2
O
1 atm
H
2
O
O
H
N
O
TFA, HOAc/MeCN
110 oC, 6 h
O
N
O
FG
FG
FG
FG
F
Br
Ph
N
O
N
O
N
O
b,c
22
, 47%
c
c
23
24
, 73%
, 67%
OMe
Ph
N
O
N
O
N
O
c
c
c
27
, 51%
O
25
, 63%
26
, 57%
OMe
O
O
CN
HO
O
O
O
28
, 46%
29
, 53%
O
30
, 45%
O
O
O
MeO
O
O
33
31
, 62%
, 66%
32
, 65%
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5
Et
H
N
O
HO
O
O
N
O
O
Et
6
7
8
9
36
, 52%
35
, 67%
34
, 70%
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12
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18
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60
H
H
N
H
N
O
Cl
O
N
O
MeO2C
Cl
Br
, 46%
37
, 65%
38
, 63%
39
O
O
O
O
O
O
c
c
40
41
, 49%
, 56%
42
, 43%
a
Reaction conditions: substrate (0.2 mmol, 1 equiv), cyclohexylboronic acid (5 equiv, 1 mmol), TFA
(2 equiv, 0.4 mmol), HOAc (0.25 mL), CH3CN (0.25 mL), 1 atm O2 (oxygen bag), 110oC (measured
temperature of the oil bath), 6 h, unless otherwise noted. Isolated yields. Only trans isomers were
observed.
b
c
As demonstrated in Scheme 4a, radical scavenger TEMPO was introduced into the
reaction of N-arylacrylamide with cyclohexylboronic acid. No alkylated oxindole was
observed, but 1-(cyclohexyloxy)-2,2,6,6-tetramethylpiperidine (43) was isolated as a
radical trapping adduct in 68% yield. In addition, 32% yield of cyclohexanol was
isolated. In accordance with the experimental results and literatures precedent, a
plausible mechanism was proposed in Scheme 4b.[2, 20] Initially, reaction of boronic
acid with molecular oxygen would afford radical A and alkyl radical. Addition of
alkyl radical to alkene followed by cyclization would give radical B. Then
hydrogen-atom transfer (HAT) from B to A would form the product and
peroxyboronic acid, which would lead to boric acid finally.
Scheme 4. Radical trap experiment and proposed mechanism.
(a)
B(OH)2
OH
O
5 equiv TEMPO
typical conditions
N
O
+
+
O
+
N
N
1 equiv
5 equiv
ND
32%
43
, 68%
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(b)
O2
RB(OH)2
+
(HO)2BOO
+
R
R
5
6
7
8
A
H
R
O
O
+
R
9
N
O
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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40
41
42
43
44
45
46
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49
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52
53
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58
59
60
N
B
R
(HO)2BOO
B(OH)3
(HO)2BOOH
O
+
N
CONCLUSIONS
In summary, we demonstrated a molecular oxygen-mediated alkylation and/or
alkylarylation of activated alkenes via autoxidation of alkylboronic acid. By simply
heating organoboronic acid under 1 atm. of oxygen, diverse functionalized
heterocycles such as oxindoles, quinolinones, chromones, coumarins and quinolones
can be efficiently synthesized. This strategy features metal-free, stoichiometric
chemical oxidant free, and high chemoselectivity. Furthermore, alphatic boronic acids
were used as the alkyl radical donors, which is far more stable and safer than other
organoboranes. Hence, the present alkylation strategy would be expected to become a
general C-C bond constructing strategy and would find wide applications in synthetic
organic chemistry.
EXPERIMENTAL SECTION
General Information: All chemicals were commercially available and used as
received without further purification. Reactions were monitored by thin-layer
1
13
19
chromatography (TLC). H NMR, C NMR, and F NMR spectra were recorded at
400, 100, and 375 MHz, respectively. Chemical shifts (δ) are given relative to internal
TMS. The NMR data are presented as follows: chemical shift (ppm), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling constant J (Hz),
and integration. HRMS spectra (ESI-TOF) were recorded in CH2Cl2 or acetonitrile.
Typical Experimental Procedure for the Synthesis of 1-42.
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A mixture of N-methyl-N-phenylmethacrylamide (1 equiv., 0.20 mmol), TFA (2
equiv., 0.40 mmol), cyclohexylboronic acid (5 equiv., 1 mmol) was dissolved in a
solution of acetic acid (0.25 mL) and acetonitrile (0.25 mL). The reaction vial was
purged with O2 for three times and then the reaction mixture was refluxing at 110oC
(measured temperature of the oil bath) for 6 hours. After the reaction finished, the
solvent was removed under reduced pressure, and purified by flash chromatography
on silica gel to afford the desired product.
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11
12
13
14
15
16
17
18
19
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21
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60
A
scaled-up
experimental
procedure:
A
mixture
of
N-methyl-N-phenylmethacrylamide (1 equiv., 8 mmol, 1.40 g), TFA (2 equiv., 16
mmol, 1.82 g), cyclohexylboronic acid (5 equiv., 40 mmol, 7.17 g) was dissolved in a
solution of acetic acid (10 mL) and acetonitrile (10 mL). The reaction vial was purged
with O2 for three times and then the reaction mixture was refluxing at 110oC
(measured temperature of the oil bath) for 6 hours. After the reaction finished, the
solvent was removed under reduced pressure, and purified by flash chromatography
on silica gel to afford the desired product (1.74 g, isolated yield: 84%).
3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one (1).19c A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1,
Yield: 90%, 46.3 mg). 1H NMR (400 MHz, CDCl3): δ 7.28 – 7.24 (m, 1H), 7.16 (d, J
= 6.8 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 3.22 (s, 3H), 1.93 (dd,
J = 14.0, 6.8 Hz, 1H), 1.72 (dd, J = 14.0, 5.2 Hz, 1H), 1.53 – 1.45 (m, 3H), 1.36 – 1.19
13
(m, 5H), 1.02 – 0.70 (m, 6H). C NMR (100 MHz, CDCl3): δ 181.1, 143.1, 134.4,
127.5, 122.7, 122.3, 107.9, 47.8, 45.4, 34.7, 34.5, 33.5, 26.2, 26.1, 26.1, 26.0. MS (EI,
m/z): 257(9.5), 161 (100), 160(32.8), 55(8.3).
3-(cyclohexylmethyl)-1,3,5-trimethylindolin-2-one (2).19c A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1,
1
Yield: 69%, 37.4 mg). H NMR (400 MHz, CDCl3): δ 7.05 (d, J = 8.0 Hz, 1H),
6.96 (s, 1H), 6.72 (d, J = 8.0 Hz, 1H), 3.19 (s, 3H), 2.35 (s, 3H), 1.91 (dd, J = 14.0, 6.8
Hz, 1H), 1.69 (dd, J = 14.0, 5.2 Hz, 1H), 1.52 – 1.46 (m, 3H), 1.36 – 1.21 (m, 5H),
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1.00 – 0.91 (m, 4H), 0.88 – 0.73 (m, 2H). C NMR (100 MHz, CDCl3): δ 181.1,
140.7, 134.5, 131.7, 127.7, 123.5, 107.6, 47.9, 45.4, 34.7, 34.5, 33.5, 26.2, 26.1, 26.0,
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21.2. MS (EI, m/z): 271(10.4), 176 (14.1), 175(100), 40(24.2).
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19c
3-(cyclohexylmethyl)-5-methoxy-1,3-dimethylindolin-2-one （ 3 ） .
A colorless
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oil after purification by flash column chromatography (petroleum ether/ethyl acetate =
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20/1, Yield: 85%, 51.5mg). H NMR (400 MHz, CDCl3):δ 6.79 – 6.72 (m, 3H),
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3.81 (s,3H), 3.19 (s, 3H), 1.92 (dd, J = 14.0, 7.2 Hz, 1H), 1.68 (dd, J = 14.0, 5.2 Hz,
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1H), 1.52 – 1.46 (m, 3H), 1.36 – 1.21 (m, 5H), 1.05 – 0.71 (m, 6H). C NMR (100
MHz, CDCl3): δ 180.7, 160.5(d, J=955), 139.0, 136.3, 113.8 (d, J=93.6), 111.0 (d,
J=96.8), 108.3 (d, J=32.4), 55.8, 48.3, 45.4, 34.7, 34.4, 33.5, 26.3, 26.1, 26.0. MS (EI,
m/z): 287(21.4), 191 (100), 190(33.6), 176(11.0).
3-(cyclohexylmethyl)-5-fluoro-1,3-dimethylindolin-2-one（4）. 19c A colorless oil
after purification by flash column chromatography (petroleum ether/ethyl acetate =
20/1, Yield: 68%, 37.4 mg). 1H NMR (400 MHz, CDCl3): δ 6.95 (td, J = 9.2, 2.4 Hz,
1H), 6.90 (dd, J = 8.0, 2.4 Hz, 1H), 6.75 (dd, J = 8.4, 4.0 Hz, 1H), 3.20 (s, 3H), 1.93
(dd, J = 14.0, 6.8 Hz, 1H), 1.68 (dd, J = 14.0, 5.2 Hz, 1H), 1.53 – 1.47 (m, 3H), 1.35 –
1.19 (m, 5H), 1.03 – 0.88 (m, 4H), 0.86 – 0.70 (m, 2H). 13C NMR (100 MHz, CDCl3):
δ 180.7, 160.5, 158.1, 139.0, 136.3, 113.8, 113.5, 111.0, 110.7, 108.3, 108.2, 48.4,
45.4, 34.7, 34.4, 33.5, 26.3, 26.1, 26.0, 26.0. MS (EI, m/z): 275(7.1), 179 (100),
178(30.2), 40(14.0).
5-chloro-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one（5）. 19c A colorless oil
after purification by flash column chromatography (petroleum ether/ethyl acetate =
20/1, Yield: 84%, 48.9 mg). 1H NMR (400 MHz, CDCl3): δ 7.23 (dd, J = 8.4, 2.0 Hz,
1H), 7.12 (d, J = 2.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.19 (s, 3H), 1.92 (dd, J = 14.0,
7.2 Hz, 1H), 1.69 (dd, J = 14.0, 5.2 Hz, 1H), 1.52 – 1.47 (m, 3H), 1.32 – 1.20 (m, 5H),
1.02 – 0.88 (m, 4H), 0.86 – 0.71 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 180.5,
141.7, 136.2, 127.7, 127.5, 123.2, 108.8, 48.1, 45.3, 34.7, 34.4, 33.4, 26.3, 26.1, 26.0,
25.9. MS (EI, m/z): 291(8.2), 197 (32.0), 195(100), 55(15.4).
5-bromo-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one（6）. 19c A colorless oil
after purification by flash column chromatography (petroleum ether/ethyl acetate =
20/1, Yield: 82%, 54.9 mg). 1H NMR (400 MHz, CDCl3): δ 7.37 (dd, J = 8.4, 2.0 Hz,
1H), 7.25 (d, J = 1.6 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 3.18 (s, 3H), 1.92 (dd, J = 14.0,
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7.2 Hz, 1H), 1.68 (dd, J = 14.0, 5.2 Hz, 1H), 1.52 – 1.47 (m, 3H), 1.32 – 1.20 (m, 5H),
1.05 – 0.88 (m, 4H), 0.86 – 0.70 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 180.4,
142.2, 136.6, 130.4, 125.9, 115.1, 109.4, 48.1, 45.3, 34.7, 34.4, 33.4, 26.3, 26.1, 26.0,
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25.9. MS (EI, m/z): 335(8.0), 239 (100), 130(12.4), 55(26.9).
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19c
3-(cyclohexylmethyl)-5-iodo-1,3-dimethylindolin-2-one （ 7 ） .
A colorless oil
after purification by flash column chromatography (petroleum ether/ethyl acetate =
1
20/1, Yield: 70%, 51.7 mg). H NMR (400 MHz, CDCl3): δ 7.57 (dd, J = 8.4, 2.0
Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 3.18 (s, 3H), 1.91 (dd, J =
14.0, 6.8 Hz, 1H), 1.68 (dd, J = 14.4, 5.2 Hz, 1H), 1.50 – 1.47 (m, 3H), 1.32 – 1.20 (m,
5H), 1.06 – 0.70 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 180.2, 142.9, 136.9, 136.4,
131.5, 110.0, 84.9, 47.9, 45.3, 34.7, 34.4, 33.4, 26.2, 26.1, 26.0, 25.9. MS (EI, m/z):
383(8.9), 287 (100), 160(14.7), 55(24.1).
19c
3-(cyclohexylmethyl)-1,3-dimethyl-2-oxoindoline-5-carbonitrile （ 8 ） .
A
colorless oil after purification by flash column chromatography (petroleum ether/ethyl
acetate = 20/1, Yield: 65%, 34.8 mg). 1H NMR (400 MHz, CDCl3): δ 7.60 (dd, J = 8.0,
1.6 Hz, 1H), 7.39 (d, J = 1.6 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 3.23 (s, 3H), 1.95 (dd,
J = 14.4, 6.8 Hz, 1H), 1.73 (dd, J = 14.4, 4.9 Hz, 1H), 1.52 – 1.46(m, 3H), 1.32 (s, 3H),
1.26 – 1.17 (m, 2H), 1.00 – 0.76 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 180.6,
146.9, 135.4, 133.0, 126.0, 119.3, 108.3, 105.3, 47.6, 45.1, 34.7, 34.3, 33.3, 26.4, 25.9,
25.9, 25.8. MS (EI, m/z): 282(4.9), 186 (100), 55(15.0), 40(51.1)
19c
3-(cyclohexylmethyl)-1,3,7-trimethylindolin-2-one （ 9 ） .
A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1,
1
Yield: 62%, 33.6 mg). H NMR (400 MHz, CDCl3): δ 6.98 – 6.91 (m, 3H), 3.49 (s,
3H), 2.59 (s, 3H), 1.91 (dd, J = 14.0, 6.8 Hz, 1H), 1.68 (dd, J = 14.0, 5.2 Hz, 1H), 1.53
– 1.46 (m, 3H), 1.38 – 1.20 (m, 5H), 1.03 – 0.69 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 181.9, 140.9, 135.1, 131.2, 122.2, 120.6, 119.5, 47.1, 45.6, 34.6, 34.5, 33.5,
29.5, 26.6, 26.1, 26.1, 26.0, 19.1. MS (EI, m/z): 271(7.5), 176 (13.2), 175(100),
40(43.8).
3-(cyclohexylmethyl)-7-methoxy-1,3-dimethylindolin-2-one（10）. 19c A colorless
oil after purification by flash column chromatography (petroleum ether/ethyl acetate =
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20/1, Yield: 82%, 44.8 mg). H NMR (400 MHz, CDCl3): δ 6.98 (t, J = 7.2 Hz, 1H),
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6.82 (d, J = 8.4 Hz, 1H), 6.77 (dd, J = 7.6, 0.8 Hz, 1H), 3.86 (s, 3H), 3.48 (s, 3H), 1.90
(dd, J = 14.0, 6.8 Hz, 1H), 1.68 (dd, J = 14.0, 5.2 Hz, 1H), 1.53 – 1.46 (m, 3H), 1.39 –
1.21 (m, 5H), 1.01 – 0.70 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 181.3, 145.3,
136.2, 130.9, 122.8, 115.5, 111.4, 55.9, 47.9, 45.5, 34.7, 34.4, 33.5, 29.4, 26.5, 26.1,
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26.0. MS (EI, m/z): 287(10.1), 191 (100), 176(7.7), 40(29.5).
19c
3-(cyclohexylmethyl)-1,3,4,6-tetramethylindolin-2-one （ 11 ） .
A colorless oil
after purification by flash column chromatography (petroleum ether/ethyl acetate =
20/1, Yield: 63%, 35.9 mg). 1H NMR (400 MHz, CDCl3): δ 6.63 (s, 1H), 6.51 (s, 1H),
3.17 (s, 3H), 2.34 (s, 3H), 2.30 (s, 3H), 1.93 (d, J = 3.6 Hz, 2H), 1.50 – 1.45 (m, 3H),
1.34 (s, 3H), 1.30 – 1.22 (m, 2H), 1.02 – 0.75 (m, 6H). 13C NMR (100 MHz, CDCl3):
δ 181.6, 143.4, 137.3, 133.8, 128.0, 125.4, 106.7, 48.4, 43.8, 35.1, 34.1, 33.0, 26.2,
26.1, 25.9, 24.2, 21.5, 18.1. MS (EI, m/z): 285(4.6), 189 (100), 188(66.5), 173(10.0).
19c
3-(cyclohexylmethyl)-5,7-dimethoxy-1,3-dimethylindolin-2-one （ 12 ） .
A
colorless oil after purification by flash column chromatography (petroleum ether/ethyl
1
acetate = 20/1, Yield: 74%, 46.9 mg). H NMR (400 MHz, CDCl3):δ 6.41 (d, J = 2.0
Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.43 (s, 3H), 1.89 (dd, J =
14.0, 6.8 Hz, 1H), 1.64 (dd, J = 14.0, 5.2 Hz, 1H), 1.53 – 1.47 (m, 3H), 1.40 – 1.23 (m,
5H), 1.06 – 0.70 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 181.0, 156.5, 145.8, 136.8,
124.5, 100.8, 98.7, 55.9, 55.8, 48.5, 45.5, 34.6, 34.4, 33.4, 29.3, 26.5, 26.1, 26.0 .MS
(EI, m/z): 317(25.1), 221 (100), 206(18.6), 55(8.9).
5-bromo-7-chloro-3-(cyclohexylmethyl)-1,3-dimethylindolin-2-one （ 13 ） . A
colorless oil after purification by flash column chromatography (petroleum ether/ethyl
acetate = 20/1, Yield: 43%, 31.7 mg). 1H NMR (400 MHz, CDCl3): δ 7.37 (dd, J = 2.0,
0.4 Hz, 1H), 7.26 (s, 1H), 7.03 (d, J = 2.0 Hz, 1H), 1.92 (dt, J = 14.0, 7.2 Hz, 1H),
1.66 (dd, J = 14.0, 5.2 Hz, 1H), 1.54 – 1.48 (m, 1H), 1.28 (s, 1H), 1.24 – 1.20 (m, 1H),
1.02 – 0.76 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 180.8, 139.2, 138.8, 132.4,
128.1, 122.2, 102.2, 47.9, 45.5, 34.5, 34.4, 33.3, 29.7, 26.6, 26.0, 25.9. HRMS
(ESI-TOF) m/z: [M+H]+ Calculated for C17H21BrClNOH 370.0568, found 370.0566.
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19c
3-(cyclohexylmethyl)-3-methyl-1-phenylindolin-2-one （ 14 ） .
A colorless oil
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after purification by flash column chromatography (petroleum ether/ethyl acetate =
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20/1, Yield: 68%, 43.4 mg). H NMR (400 MHz, CDCl3): δ 7.52 (t, J = 8.0 Hz, 2H),
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7.41 – 7.38 (m, 3H), 7.25 – 7.16 (m, 2H), 7.09 (t, J = 7.2 Hz, 1H), 6.83 (d, J = 8.0 Hz,
1H), 2.03 (dd, J = 14.0, 7.2 Hz, 1H), 1.80 (dd, J = 14.0, 5.2 Hz, 1H), 1.56 – 1.50 (m,
3H), 1.44 (s, 3H), 1.29 (d, J = 12.4 Hz, 1H), 1.14 – 0.75 (m, 7H). 13C NMR (100 MHz,
CDCl3): δ 180.4, 143.0, 134.8, 134.2, 129.5, 127.8, 127.4, 126.4, 123.0, 122.8, 109.3,
47.9, 45.8, 34.9, 34.4, 33.6, 26.4, 26.2, 26.1, 26.0. MS (EI, m/z): 319(7.3), 223 (100),
194(7.0), 40(39.0).
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3-(cyclohexylmethyl)-1,3-dimethyl-1,3-dihydro-2H-benzo[g]indol-2-one（15）. 19c
A colorless oil after purification by flash column chromatography (petroleum
1
ether/ethyl acetate = 20/1, Yield: 64%, 39.3 mg). H NMR (400 MHz, CDCl3): δ
7.71 (d, J = 8.0 Hz, 1H), 7.55 – 7.50 (m, 2H), 7.44 – 7.38 (m, 2H), 6.94 (d, J = 7.2 Hz,
1H), 3.53 (s, 3H), 2.41 (dd, J = 14.0, 7.6 Hz, 1H), 1.87 (dd, J = 14.0, 4.8 Hz, 1H), 1.63
13
(s, 3H), 1.45 – 1.18 (m, 5H), 1.14 – 0.72 (m, 6H). C NMR (100 MHz, CDCl3): δ
173.8, 138.5, 136.9, 133.3, 126.8, 126.2, 125.6, 123.1, 122.3, 119.6, 108.0, 51.0, 46.5,
34.8, 34.5, 33.3, 32.9, 29.6, 26.2, 26.1. MS (EI, m/z): 307(8.6), 211 (100), 182(32.6),
55(8.6).
19c
(3-(cyclohexylmethyl)-1-methyl-2-oxoindolin-3-yl)methyl acetate （ 16 ） .
A
colorless oil after purification by flash column chromatography (petroleum ether/ethyl
acetate = 20/1, Yield: 72%, 45.4mg). 1H NMR (400 MHz, CDCl3): δ 7.29 (td, J = 7.6,
1.2 Hz, 1H), 7.18 (d, J = 7.2 Hz, 1H), 7.05 (t, J = 7.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H),
4.43 (d, J = 10.8 Hz, 1H), 4.08 (d, J = 10.8 Hz, 1H), 3.23 (s, 3H), 1.87 (dd, J = 14.0,
7.2 Hz, 1H), 1.82 (s, 3H), 1.76 (dd, J = 14.0, 5.2 Hz, 1H), 1.52 – 1.42 (m, 3H), 1.33 (d,
13
J = 13.2 Hz, 1H), 1.25 – 1.20 (m, 1H), 1.05 – 0.71 (m, 6H). C NMR (100 MHz,
CDCl3): δ 178.0, 170.3, 144.0, 129.8, 128.3, 123.6, 122.4, 107.9, 68.4, 51.9, 40.2,
34.4, 34.0, 33.5, 26.3, 26.0, 25.9, 20.5. MS (EI, m/z): 315(6.6), 159 (100), 130(7.5),
40(17.3).
1,3-dimethyl-3-propylindolin-2-one（17）. 13 A colorless oil after purification by
flash column chromatography (petroleum ether/ethyl acetate = 20/1, Yield: 60%, 24.4
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mg). 1H NMR (400 MHz, CDCl3): δ 7.26 (td, J = 6.8, 1.2 Hz, 1H), 7.17 (dd, J = 7.2,
0.8 Hz, 1H), 7.06 (td, J = 7.6, 1.2 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 3.21 (s, 3H),
1.84–1.91 (m, 1H), 1.74 – 1.66 (m, 1H), 1.35 (s, 3H), 1.04 – 0.96 (m, 1H), 0.90 – 0.82
(m, 1H), 0.77 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 180.9, 143.3, 134.3,
127.5, 122.5, 122.4, 107.8, 48.5, 40.8, 26.0, 23.7, 17.8, 14.1. MS (EI, m/z): 203(30.5),
161 (100), 160(94.2), 40(58.4).
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3-butyl-1,3-dimethylindolin-2-one（18）. A colorless oil after purification by
flash column chromatography (petroleum ether/ethyl acetate = 20/1, Yield: 78%, 33.9
1
mg). H NMR (400 MHz, CDCl3): δ 7.28 – 7.24(m, 1H), 7.16 (d, J = 7.2 Hz, 1H),
7.06 (t, J = 7.2 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 3.21 (s, 3H), 1.89 (td, J = 13.2, 4.8
Hz, 1H), 1.72 (td, J = 12.8, 4.4 Hz, 1H), 1.34 (s, 3H), 1.13–1.22 (m, 2H), 0.92–0.98
(m, 1H), 0.84 – 0.80 (m, 1H), 0.77 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 181.0, 143.2, 134.2, 127.5, 122.8, 122.2, 107.8, 48.2, 46.0, 33.9, 33.5, 32.2, 27.1,
27.0, 26.3, 26.1, 25.6, 25.1, 24.9. MS (EI, m/z): 217(27.8), 161 (100), 160(83.4),
132(14.3).
3-isobutyl-1,3-dimethylindolin-2-one（19）. 13 A colorless oil after purification by
flash column chromatography (petroleum ether/ethyl acetate = 20/1, Yield: 75%, 32.6
1
mg). H NMR (400 MHz, CDCl3): δ 7.24 (td, J = 7.2, 1.2 Hz, 1H), 7.15 – 7.12 (m,
1H), 7.04 (td, J = 7.2, 0.8 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 3.19 (s, 3H), 1.92 (dd, J =
13.6, 7.6 Hz, 1H), 1.74 (dd, J = 13.6, 5.2 Hz, 1H), 1.30 (s, 3H), 1.23 (dt, J = 12, 6.4
13
Hz, 1H), 0.63 (d, J = 6.4 Hz, 3H), 0.58 (d, J = 6.8 Hz, 3H). C NMR (100 MHz,
CDCl3): δ 181.0, 143.1, 134.1, 127.5, 122.7, 122.3, 107.9, 48.0, 46.7, 26.1, 26.1, 25.5,
24.1, 22.8. MS (EI, m/z): 217(19.6), 161 (100), 160(74.9), 132(11.6).
1,3-dimethyl-3-pentylindolin-2-one（20）. 13 A colorless oil after purification by
flash column chromatography (petroleum ether/ethyl acetate = 20/1, Yield: 61%, 28.2
mg). 1H NMR (400 MHz, CDCl3): δ 7.26 (td, J = 7.6, 1.2 Hz, 1H), 7.16 (dd, J = 7.2,
1.2 Hz, 1H), 7.06 (td, J = 7.2, 0.8 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.19 (s, 3H), 1.87
(ddd, J = 13.2, 12.4, 4.8 Hz, 1H), 1.75 – 1.67 (m, 1H), 1.34 (s, 3H), 1.17 – 1.10(m,
13
4H), 1.02 – 0.92 (m, 1H), 0.86 – 0.80 (m, 1H), 0.77 (dd, J = 6.8, 2.8 Hz, 3H). C
NMR (100 MHz, CDCl3): δ 180.1, 143.3, 134.3, 127.5, 122.4, 122.3, 107.8, 48.4,
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38.45, 31.9, 26.0, 24.0, 23.7, 22.3, 13.9. MS (EI, m/z): 231(20.0), 161 (100),
160(67.4), 132(10.4).
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3-(cyclobutylmethyl)-1,3-dimethylindolin-2-one （ 21 ） . A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1,
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Yield: 57%, 26.1 mg). H NMR (400 MHz, CDCl3)：δ 7.27 – 7.23 (m, 1H), 7.17 –
7.14 (m, 1H), 7.04 (td, J = 7.6, 1.2 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 3.19 (s, 3H),
2.04 (dd, J = 12.4, 6.0 Hz, 1H), 1.85 (dd, J = 13.2, 6.8 Hz, 1H), 1.72 – 1.67 (m, 1H),
1.65 – 1.53 (m, 4H), 1.47 – 1.36 (m, 2H), 1.31 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 180.8, 143.2, 134.1, 127.5, 122.8, 122.2, 107.7, 47.9, 45.5, 32.9, 29.4, 28.8, 26.1,
23.9, 18.8. HRMS (ESI-TOF) m/z: [M+H]+ Calculated for C15H19NOH 230.1539,
found 230.1537.
3-cyclohexyl-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one（22）. A colorless
oil after purification by flash column chromatography (petroleum ether/ethyl acetate =
10/1, Yield: 47%, 30.0 mg). 1H NMR (400 MHz, CDCl3): δ 7.33 (m, 1H), 7.19 (dt, J
= 13.2, 7.6 Hz, 4H), 7.10 – 7.04 (m, 2H), 6.96 (d, J = 7.6 Hz, 2H), 4.22 (s, 1H), 3.36
(s, 3H), 2.67 (d, J = 8.8 Hz, 1H), 1.92 (d, J = 10.0 Hz, 1H), 1.69 (d, J = 10.8 Hz, 2H),
1.58 (s, 2H), 1.49 – 0.84 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 170.5, 142.3, 140.0,
129.6, 128.7, 128.0, 127.0, 126.6, 123.2, 114.8, 55.6, 44.4, 37.6, 31.4, 31.1, 29.4, 26.1,
26.1, 25.9. HRMS (ESI-TOF) m/z: [M+H]+ Calculated for C22H25NOH 320.2009,
found 320.2007.
3-cyclohexyl-4-(4-fluorophenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one （ 23 ） .
A colorless oil after purification by flash column chromatography (petroleum
ether/ethyl acetate = 10/1, Yield: 67%, 45.2 mg). 1H NMR (400 MHz, CDCl3): δ 7.48
– 7.30 (m, 1H), 7.23 – 7.14 (m, 1H), 7.10 – 7.03 (m, 2H), 6.94 – 6.86 (m, 4H), 4.19 (s,
1H), 3.35 (s, 3H), 2.63 (dd, J = 9.2, 1.6 Hz, 1H), 1.91 (d, J = 9.6 Hz, 1H), 1.79 – 1.64
(m, 2H), 1.56 (d, J = 11.6 Hz, 2H), 1.44 – 0.93 (m, 6H). 13C NMR (100 MHz, CDCl3):
δ 170.3, 162.7, 160.3, 139.9, 137.9, 129.5, 128.6 (d, J=31.4), 128.1, 126.4, 123.3,
115.5, 115.3, 114.9, 55.7, 43.6, 37.5, 31.3, 31.0, 29.4, 26.1, 25.9. HRMS (ESI-TOF)
m/z: [M+H]+ Calculated for C22H24FNOH 338.1915, found 338.1909.
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4-(4-bromophenyl)-3-cyclohexyl-1-methyl-3,4-dihydroquinolin-2(1H)-one （24 ）.
A colorless oil after purification by flash column chromatography (petroleum
ether/ethyl acetate = 10/1, Yield: 73%, 58.0 mg). 1H NMR (400 MHz, CDCl3): δ 7.36
– 7.29 (m, 3H), 7.16 (d, J = 7.6 Hz, 1H), 7.07 (dd, J = 7.4, 6.4 Hz, 2H), 6.82 (d, J =
8.0 Hz, 2H), 4.16 (s, 1H), 3.35 (s, 3H), 2.61 (d, J = 8.8 Hz, 1H), 1.90 (d, J = 10.8 Hz,
1H), 1.79 – 1.50 (m, 5H), 1.38 – 1.02 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 170.1,
141.2, 139.9, 131.7, 129.5, 128.8, 128.3, 126.0, 123.3, 120.5, 114.9, 55.5, 43.8, 37.5,
31.3, 31.0, 29.5, 26.0, 25.9. HRMS (ESI-TOF) m/z: [M+H]+ Calculated for
C22H24BrNOH 398.1114, found 398.1112.
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3-cyclohexyl-1-methyl-4-(p-tolyl)-3,4-dihydroquinolin-2(1H)-one （ 25 ） . A
colorless oil after purification by flash column chromatography (petroleum ether/ethyl
acetate = 10/1, Yield: 63%, 42.0 mg). 1H NMR (400 MHz, CDCl3): δ 7.32 (t, J = 6.8
Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 7.10 – 6.99 (m, 4H), 6.85 (d, J = 7.6 Hz, 2H), 4.18
(s, 1H), 3.36 (s, 3H), 2.65 (d, J = 8.4 Hz, 1H), 2.25 (s, 3H), 1.92 (d, J = 10.0 Hz, 1H),
13
1.69 (m, 2H), 1.56 (d, J = 12.4 Hz, 2H), 1.41 – 1.02 (m, 6H). C NMR (100 MHz,
CDCl3): δ 170.6, 134.0, 139.2, 136.1, 129.5, 129.3, 127.9, 126.9, 126.9, 123.2, 114.8,
55.6, 44.0, 37.6, 31.4, 31.1, 29.4, 26.1, 25.9, 20.9. HRMS (ESI-TOF) m/z: [M+H]+
Calculated for C23H27NOH 334.2165, found 334.2162.
3-cyclohexyl-4-(4-methoxyphenyl)-1-methyl-3,4-dihydroquinolin-2(1H)-one（26）.
A colorless oil after purification by flash column chromatography (petroleum
ether/ethyl acetate = 10/1, Yield: 57%, 39.8 mg). 1H NMR (400 MHz, CDCl3): δ 7.33
(td, J = 8.0, 1.6 Hz, 1H), 7.18 (dd, J = 7.6, 1.2 Hz, 1H), 7.06 (dd, J = 6.8, 4 Hz, 2H),
6.87 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 4.16 (s, 1H), 3.73 (s, 3H), 3.35 (s,
3H), 2.64 (dd, J = 9.2, 1.6 Hz, 1H), 1.91 (d, J = 10.4 Hz, 1H), 1.69 (m, 2H), 1.56 (d, J
13
= 12.4 Hz, 2H), 1.20 (m, 6H). C NMR (100 MHz, CDCl3): δ 170.7, 158.1, 139.9,
134.2, 129.5, 128.0, 127.9, 127.0, 123.2, 114.8, 114.0, 55.7, 55.2, 43.5, 37.5, 31.4,
31.1, 29.5, 26.1, 25.9. HRMS (ESI-TOF) m/z: [M+H]+ Calculated for C23H27NO2H
350.2115, found 350.2111.
3-cyclohexyl-1,8-dimethyl-4-phenyl-3,4-dihydroquinolin-2(1H)-one （ 27 ） . A
colorless oil after purification by flash column chromatography (petroleum ether/ethyl
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acetate = 10/1, Yield: 51%, 34.0 mg). 1H NMR (400 MHz, CDCl3): δ 7.23 (d, J = 7.6
Hz, 2H), 7.17 (dd, J = 7.2, 1.2 Hz, 2H), 7.07 – 7.02 (m, 2H), 7.02 – 6.97 (m, 2H), 4.13
(s, 1H), 3.23 (s, 3H), 2.67 (dd, J = 9.6, 1.6 Hz, 1H), 2.40 (s, 3H), 1.85 (d, J = 8.8 Hz,
1H), 1.71 – 1.54 (m, 4H), 1.35 – 0.92 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 173.4,
151.1, 141.6, 141.2, 141.2, 131.6, 129.8, 128.6, 127.7, 127.2, 127.0, 126.6, 124.5,
56.9, 44.8, 36.4, 35.8, 31.6, 31.0, 26.1, 25.9, 25.8, 20.9. HRMS (ESI-TOF) m/z:
[M+H]+ Calculated for C23H27NOH 334.2165, found 334.2162.
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3-cyclohexyl-4H-chromen-4-one（28）. A colorless oil after purification by flash
column chromatography (petroleum ether/ethyl acetate = 20/1, Yield: 46%, 21.0 mg).
1H NMR (400 MHz, CDCl3): δ 8.32 – 8.09 (m, 1H), 7.71 – 7.56 (m, 1H), 7.43 (d, J =
8.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H) , 6.19 (s, 1H), 2.53 (t, J = 11.6 Hz, 1H), 2.03 (d,
J = 12.4 Hz, 2H), 1.82 (m, 3H), 1.59 – 1.25 (m, 5H). 13C NMR (100 MHz, CDCl3): δ
178.8, 173.5, 156.4, 133.4, 125.6, 124.8, 123.7, 117.8, 107.8, 42.8, 30.4, 25.8, 25.7.
HRMS (ESI-TOF) m/z: [M+H]+ Calculated for C15H16O2H 229.1221, found
229.1223.
2-cyclohexyl-4-oxo-4H-chromene-3-carbonitrile （ 29 ） . A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1,
Yield: 53%, 26.8 mg). 1H NMR (400 MHz, CDCl3): δ 8.22 (dd, J = 8.0, 1.2 Hz, 1H),
7.83 – 7.69 (m, 1H), 7.49 (dd, J = 13.2, 7.6 Hz, 2H), 3.15 (tt, J = 12.0, 3.2 Hz, 1H),
2.10 – 1.87 (m, 4H), 1.84 – 1.67 (m, 3H), 1.53 – 1.26 (m, 4H). 13C NMR (100 MHz,
CDCl3): δ 181.0, 173.7, 155.4, 134.8, 126.6, 126.1, 122.3, 118.0, 113.1, 98.8, 43.6,
29.6, 25.4, 25.3. HRMS (ESI-TOF) m/z: [M+H]+ Calculated for C16H15NO2H
254.1176, found 254.1180.
2-cyclohexyl-6-hydroxy-3-(4-methoxyphenyl)-4H-chromen-4-one （ 30 ） . A
colorless oil after purification by flash column chromatography (petroleum ether/ethyl
1
acetate = 5/1, Yield: 45%, 31.5 mg). H NMR (400 MHz, CDCl3): δ 7.88 – 7.81 (m,
2H), 7.14 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 6.0, 3.6 Hz, 3H), 6.72 (dd, J = 8.4, 2.0 Hz,
1H), 5.45 (s, 1H), 3.89 (s, 3H), 3.01 (tt, J = 12.0, 3.6 Hz, 1H), 1.90 (d, J = 12.8 Hz,
13
2H), 1.83 – 1.77 (m, 2H), 1.71 (dd, J = 12.4, 3.2 Hz, 2H), 1.35 – 1.17 (m, 4H). C
NMR (100 MHz, CDCl3): δ 191.0, 167.4, 163.5, 154.3, 153.6, 131.9, 131.7, 121.5,
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120.6, 115.1, 113.6, 112.2, 98.1, 55.5, 37.4, 31.2, 26.1, 25.7. HRMS (ESI-TOF) m/z:
[M+H]+ Calculated for C22H22O4H 351.1591, found 351.1600.
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3-cyclohexyl-2H-chromen-2-one（31）.15 A colorless oil after purification by flash
column chromatography (petroleum ether/ethyl acetate = 20/1, Yield: 66%, 30.1 mg).
1H NMR (400 MHz, CDCl3): δ 7.48 (t, J =6.8 Hz, 3H), 7.33 (d, J = 8.0 Hz, 1H), 7.29
(d, J = 6.8 Hz, 1H), 2.81 (t, J = 12.0 Hz, 1H), 2.01 (d, J = 11.6 Hz, 2H), 1.84 (m, 3H),
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1.48 (m, 12.8 Hz, 2H), 1.38 – 1.27 (m, 3H). C NMR (100 MHz, CDCl3): δ 161.6,
152.6, 136.3, 134.8, 130.4, 127.3, 124.1, 119.6, 116.3, 38.1, 32.1, 26.5, 26.1. MS (EI,
m/z): 115(47.8), 160 (86.4), 172(96.8), 228(100).
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3-cyclohexyl-7-methyl-2H-chromen-2-one （ 32 ） .
A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1,
1
Yield: 65%,31.5 mg). H NMR (400 MHz, CDCl3): δ 7.39 (s, 1H), 7.26 – 7.21 (m,
2H), 7.18 (d, J = 8.4 Hz, 1H), 2.76 (m, 1H), 2.38 (s, 3H), 1.96 (d, J = 12.0 Hz, 2H),
1.88 – 1.73 (m, 3H), 1.32 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 161.8, 150.7,
136.3, 134.6, 133.7, 131.4, 127.1, 119.3, 115.9, 38.0, 32.1, 26.5, 26.1, 20.8. MS (EI,
m/z): 128(25.3), 174 (88.6), 186(88.2), 242(100).
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3-cyclohexyl-7-methoxy-2H-chromen-2-one （ 33 ） .
A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1,
1
Yield: 62%, 32.0 mg). H NMR (400 MHz, CDCl3): δ 7.38 (s, 1H), 7.32 (d, J = 8.4
Hz, 1H), 6.80 (m, 2H), 3.84 (s, 3H), 2.71 (t, J = 12.0 Hz, 1H), 1.94 (d, J = 11.6 Hz,
13
2H), 1.82 (d, J = 13.2 Hz, 2H), 1.75 (d, J = 12.8 Hz, 1H), 1.49 – 1.19 (m, 5H). C
NMR (100 MHz, CDCl3): δ 161.9, 161.6, 154.2, 136.4, 131.0, 128.1, 113.2, 112.2,
100.2, 55.6, 37.9, 32.1, 26.5, 26.1. MS (EI, m/z): 77(15.2), 177 (100), 189(70.4),
258(67.2).
3-cyclohexyl-7-hydroxy-4-methyl-2H-chromen-2-one（34）. A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1,
1
Yield: 70%, 36.1 mg). H NMR (400 MHz, CDCl3): δ 8.94 (s, 1H), 7.51 (d, J = 8.8
Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 8.8, 2.4 Hz, 1H), 2.87 (t, J = 12.0 Hz,
1H), 2.43 (s, 3H), 2.16 (dd, J = 13.2, 10.0 Hz, 2H), 1.83 (d, J = 4.8 Hz, 2H), 1.70 (s,
13
1H), 1.55 (d, J = 12.4 Hz, 2H), 1.32 (s, 3H). C NMR (100 MHz, CDCl3): δ 162.2,
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159.2, 153.3, 147.6, 126.2, 126.1, 113.9, 113.4, 102.7, 39.5, 29.2, 26.9, 25.7, 15.0.
HRMS (ESI-TOF) m/z: [M+H]+ Calculated for C16H18O3H 259.1329, found
259.1325.
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3-cyclohexyl-7-(diethylamino)-4-methyl-2H-chromen-2-one（35）. A colorless oil
after purification by flash column chromatography (petroleum ether/ethyl acetate =
20/1, Yield: 67%, 41.9 mg). 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J = 9.2 Hz, 1H),
6.55 (dd, J = 8.8, 2.4 Hz, 1H), 6.44 (d, J = 2.8 Hz, 1H), 3.37 (q, J = 7.2 Hz, 4H), 2.80
(t, J = 12.0 Hz, 1H), 2.35 (s, 3H), 2.25 – 2.09 (m, 2H), 1.89 – 1.77 (m, 2H), 1.67 (d, J
= 4.0 Hz, 1H), 1.52 (d, J = 12.8 Hz, 2H), 1.31 (t, J = 6.4 Hz, 3H), 1.16 (t, J = 7.2 Hz,
6H). 13C NMR (100 MHz, CDCl3): δ 161.2, 154.5, 149.2, 146.1, 125.5, 123.9, 109.7,
108.1, 97.1, 44.6, 39.3, 29.3, 27.0, 25.7, 14.5, 12.4. HRMS (ESI-TOF) m/z: [M+H]+
Calculated for C20H27NO2H 314.2115, found 314.2110.
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3-cyclohexylquinolin-2(1H)-one（36）. A colorless oil after purification by flash
column chromatography (petroleum ether/ethyl acetate = 20/1, Yield: 52%, 23.6 mg).
1H NMR (400 MHz, CDCl3): δ 11.80 (s, 1H), 7.60 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H),
7.47 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 3.05 (t, J =
11.6 Hz, 1H), 2.04 (d, J = 11.6 Hz, 2H), 1.90 (d, J = 12.8 Hz, 2H), 1.62 – 1.48 (m,
2H), 1.46 – 1.25 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 163.8, 139.2, 137.0, 134.3,
129.2, 127.2, 122.2, 120.4, 115.4, 37.1, 32.6, 26.7, 26.4. HRMS (ESI-TOF) m/z:
[M+H]+ Calculated for C15H17NOH 228.1383, found 228.1387.
methyl 3-cyclohexyl-2-oxo-1,2-dihydroquinoline-6-carboxylate（37）. A colorless
oil after purification by flash column chromatography (petroleum ether/ethyl acetate =
10/1, Yield: 65%, 37.1 mg). 1H NMR (400 MHz, CDCl3): δ 12.23 (s, 1H), 8.26 (d, J =
1.2 Hz, 1H), 8.10 (dd, J = 8.4, 1.6 Hz, 1H), 7.62 (s, 1H), 7.41 (d, J = 8.8 Hz, 1H), 3.94
(s, 3H), 2.99 (t, J = 11.6 Hz, 1H), 1.99 (d, J = 12.0 Hz, 2H), 1.87 (d, J = 12.8 Hz, 2H),
1.50 (dd, J = 25.6, 12.8 Hz, 2H), 1.40 – 1.22 (m, 4H). 13C NMR (100 MHz, CDCl3): δ
166.5, 164.2, 140.0, 134.6, 130.0, 129.7, 124.2, 119.8, 115.5, 52.2, 37.2, 32.4, 26.7,
26.3. HRMS (ESI-TOF) m/z: [M+H]+ Calculated for C17H19NO3H 286.1438, found
286.1447).
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4,7-dichloro-3-cyclohexylquinolin-2(1H)-one （ 38 ） . A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 10/1,
Yield: 63%, 37.2 mg). 1H NMR (400 MHz, DMSO): δ 11.16 (s, 1H), 7.03 (d, J = 8.8
Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 6.44 (dd, J = 8.8, 2.0 Hz, 1H), 2.39 (t, J = 11.6 Hz,
1H), 1.49 – 1.26 (m, 2H), 0.94 (d, J = 12.4 Hz, 2H), 0.65 (d, J = 12.8 Hz, 2H), 0.54 –
0.34 (m, 4H). 13C NMR (100 MHz, DMSO): δ 160.5, 139.8, 138.2, 135.8, 135.5,
127.5, 122.9, 117.2, 114.6, 28.3, 26.4, 25.9. HRMS (ESI-TOF) m/z: [M+H]+
Calculated for C15H15Cl2NOH 296.0603, found 296.0613.
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4-(bromomethyl)-3-cyclohexylquinolin-2(1H)-one （ 39 ） . A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 20/1,
1
Yield: 46%, 29.3mg). H NMR (400 MHz, CDCl3):δ 11.75 (s, 1H), 7.75 – 7.69 (m,
1H), 7.47 – 7.41 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.23 – 7.14 (m, 1H), 2.54 (s, 2H),
2.38 (d, J = 4.4 Hz, 1H), 1.88 (d, J = 6.0 Hz, 2H), 1.76 (s, 2H), 1.61 (d, J = 12.8 Hz,
2H), 1.40 (t, J = 8.2 Hz, 3H), 1.26 (t, J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ
163.4, 142.6, 137.0, 135.0, 129.0, 124.5, 121.9, 121.2, 115.5, 33.6, 29.4, 27.3, 26.2,
15.2. HRMS (ESI-TOF) m/z: [M+H]+ Calculated for C16H18BrNOH 320.0645, found
320.0649.
2,3-dicyclohexyl-2,3-dihydronaphthalene-1,4-dione （ 40 ） . A colorless oil after
purification by flash column chromatography (petroleum ether/ethyl acetate = 100/1,
Yield: 56%, 36.3 mg). 1H NMR (400 MHz, CDCl3): δ 7.98 (dd, J = 6.0, 3.6 Hz, 2H),
7.72 (dd, J =6.0, 3.6 Hz, 2H), 2.82 (d, J = 8.4 Hz, 2H), 1.87 (d, J = 12.4 Hz, 2H), 1.70
– 1.55 (m, 6H), 1.50 – 1.37 (m, 4H), 1.18 – 0.92 (m, 10H). 13C NMR (100 MHz,
CDCl3): δ 199.9, 134.6, 134.2, 126.5, 58.1, 40.4, 31.6, 31.0, 26.0, 25.9, 25.9. HRMS
(ESI-TOF) m/z: [M+H]+ Calculated for C22H28O2H 325.2162, found 325.2172.
2,3-dicyclohexyl-2-methyl-2,3-dihydronaphthalene-1,4-dione （ 41 ） . A colorless
oil after purification by flash column chromatography (petroleum ether/ethyl acetate =
1
100/1, Yield: 49%, 33.1 mg). H NMR (400 MHz, CDCl3): δ 7.98 – 7.94 (m, 1H),
7.90 – 7.86 (m, 1H), 7.70 – 7.64 (m, 2H), 2.78 (d, J = 2.0 Hz, 1H), 2.24 (d, J = 11.6
Hz, 1H), 2.15 (t, J = 11.6 Hz, 1H), 1.88 – 1.61 (m, 6H), 1.55 – 1.42 (m, 4H), 1.41 –
1.12 (m, 6H), 1.11 (s, 3H), 1.08 – 0.84 (m, 4H). 13C NMR (100 MHz, CDCl3): δ 203.1,
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199.4, 135.9, 135.1, 134.0, 133.3, 126.6, 125.5, 64.3, 52.2, 39.7, 36.7, 32.8, 31.6, 30.1,
29.2, 27.0, 26.9, 26.9, 26.8, 26.8, 26.3, 25.6, 21.9. HRMS (ESI-TOF) m/z: [M+H]+
Calculated for C23H30O2H 339.2319, found 339.2328.
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2,3-dicyclohexylnaphthalene-1,4-dione（42）. A colorless oil after purification by
flash column chromatography (petroleum ether/ethyl acetate = 20/1, Yield: 43%, 27.7
mg). 1H NMR (400 MHz, CDCl3): δ 7.99 (dd, J = 6.0, 3.6 Hz, 2H), 7.65 (dd, J = 6.0,
3.6 Hz, 2H), 3.07 (t, J = 11.6 Hz, 2H), 2.09 – 2.00 (m, 4H), 1.91 – 1.72 (m, 6H), 1.60
(d, J = 12.4 Hz, 4H), 1.35 (s, 6H). 13C NMR (100 MHz, CDCl3): δ185.9, 150.8, 133.0,
132.5, 125.9, 39.7, 30.5, 27.1, 25.9. HRMS (ESI-TOF) m/z: [M+H]+ Calculated for
C22H26O2H 323.2006, found 323.2016.
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1-(cyclohexyloxy)-2,2,6,6-tetramethylpiperidine
(43).
A
mixture
of
N-methyl-N-phenylmethacrylamide (1 equiv., 0.20 mmol), TFA (2 equiv., 0.40 mmol),
cyclohexylboronic acid (5 equiv., 1 mmol) and TEMPO (5 eq, 1 mmol) was dissolved
in a solution of acetic acid (0.25 mL) and acetonitrile (0.25 mL). The reaction vial
was purged with O2 for three times and then the reaction mixture was reflux at 110oC
(measured temperature of the oil bath) for 6 hours. After the reaction finished, the
solvent was removed under reduced pressure, and purified by flash chromatography
on silica gel to afford cyclohexanol and 43 as a colorless oil (petroleum ether/ethyl
1
acetate =60/1- 20/1, Yield: 68%, 32.5 mg). H NMR (400 MHz, CDCl3): δ 4.16 –
3.02 (m, 1H), 2.05 (dd, J = 9.6, 4.2 Hz, 2H), 1.73 (d, J = 2.8 Hz, 2H), 1.53 (d, J = 5.2
13
Hz, 6H), 1.45 (s, 4H), 1.21 (t, J = 10.0 Hz, 4H), 1.12 (s, 13H). C NMR (100 MHz,
CDCl3): δ 81.7, 59.6, 40.3, 32.9, 26.0, 25.1, 17.3. HRMS (ESI-TOF) m/z: [M+H]+
Calculated for C15H29NOH 240.2322, found 240.2330.
AUTHOR INFORMATION
Corresponding Author:
E-mail: liuzhq@lzu.edu.cn
Notes
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The authors declare no competing financial interest.
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Supporting Information
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Experimental procedures, mechanistic studies, and characterization and spectral data.
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This material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
This project is supported by National Natural Science Foundation of China (No.
21672089, 21472080) and the Natural Science Foundation of the Jiangsu Higher
Education Institutions of China (No. 17KJA350001).
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